Translational Research

Translational research facilitates the movement of new ideas and
treatments from the laboratory to the clinic, as well as the movement of
clinical observations from the clinic to the laboratory.

Translational research facilitates the movement of new ideas and
treatments from the laboratory to the clinic, as well as the movement of
clinical observations from the clinic to the laboratory.

Transcending boundaries

The aim of our institution is to advance the progress of research for the clinical benefit of our patients by fostering and expanding multidisciplinary collaborative interactions among MD Anderson faculty and with external companies and institutions.

Researchers at The University of Texas MD Anderson Cancer Center have
identified a tenacious subset of immune macrophages that thwart
treatment of glioblastoma with anti-PD-1 checkpoint blockade,
elevating a new potential target for treating the almost uniformly
lethal brain tumor.

Their findings, reported in Nature Medicine, identify macrophages
that express high levels of CD73, a surface enzyme that’s a vital
piece of an immunosuppressive molecular pathway. The strong presence
of the CD73 macrophages was unique to glioblastoma among five tumor
types analyzed by the researchers.

After establishing the cells’ presence in human tumors and
correlating them with decreased survival, the researchers took their
hypothesis to a mouse model of glioblastoma. They found combining
anti-PD-1 and anti-CTLA-4 immunotherapies
in CD73 knockout mice stifled tumor growth and increased survival.

“We’re working with pharmaceutical companies that are developing
agents to target CD73 to move forward with a glioblastoma clinical
trial in combination with anti-PD-1 and anti-CTLA-4 checkpoint
inhibitors,” says Padmanee
Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology
and Immunology.

Sharma and colleagues take an approach they call reverse
translation. Instead of developing hypotheses through cell line and
animal model experiments that are then translated to human clinical
trials, the team starts by analyzing human tumors to generate
hypotheses for testing in the lab in hopes of then taking findings to
human clinical trials.

To more effectively extend immunotherapy to more cancers, Sharma
says, researchers need to realize immune microenvironments differ from
cancer to cancer. “Understanding what’s different in immune niches
across cancers provides clues and targets for treating tumors,” Sharma
says. “That’s why we did this study.”

The team tracked down the population of CD73-positive macrophages
through a project to characterize immune cells found in five tumor
types using CyTOF mass cytometry and single-cell RNA sequencing. They
analyzed 94 human tumors across glioblastoma, non-small cell lung
cancer and kidney, prostate and colorectal cancers to characterize
clusters of immune cells.

CD73 cells associated with shorter survival

The most surprising finding was a metacluster of immune cells found
predominantly among the 13 glioblastoma tumors. Cells in the cluster
expressed CD68, a marker for macrophages, immune system cells that
either aid or suppress immune response. The CD68 metacluster also
expressed high levels of CD73 as well as other immune-inhibiting
molecules. The team confirmed these findings in nine additional glioblastomas.

Single-cell RNA sequencing identified an immunosuppressive gene
expression signature associated with the high-CD73-expressing
macrophages. A refined gene signature for the cells was evaluated
against 525 glioblastoma samples from The Cancer Genome Atlas and was
correlated with decreased survival.

The team treated mice with either PD-1 inhibitors or a combination
of PD-1 and CTLA-4 immune checkpoint inhibitors. Mice with intact
CD73 treated with the combination had increased survival over
untreated mice, while mice with CD73 knocked out lived even longer
after combination therapy. There was no survival benefit from
anti-PD-1 alone.

“Based on our data and earlier studies, we propose a combination
therapy strategy to target CD73 plus dual blockade of PD-1 and
CTLA-4,” the team concludes in the paper, noting that anti-CD73
antibodies have yielded promising results in early studies.